Cocaine tends not to be immediately addictive. Current estimates place the percentage of persons in the United States who have become dependent on cocaine at about 7% (more than 2 million individuals so far) of those who ever use the drug. The factors that lead to dependence have not been identified, but clinical evidence suggests that a prolonged period of intermittent use of the drug often precedes the development of dependence. The proposed research is aimed at furthering our knowledge concerning behavioral effects of relatively long-term intermittent exposure to cocaine. Laboratory study of effects of long-term intermittent exposure to cocaine has yielded a puzzling array of results. Sometimes tolerance is observed, sometimes sensitization. Also effects of terminating a long series of administrations of cocaine (i.e., drug withdrawal) have ranged from a dependency syndrome to no effect. Previous research, however, has indicated that experiential/behavioral factors can determine whether or not tolerance occurs to cocaine's effects or whether effects of the drug persist after if is withdrawn. The proposed research is aimed at adding to our knowledge of how experiential factors interact with repeated cocaine exposure. The specific aims of this application follow mainly from our previous research, and in each study operant behavior of either pigeons or squirrel monkeys will be examined. In the proposed studies we shall 1) compare intermittent exposure to a fixed dose with intermittent exposure to variable doses; 2) assess the magnitude of tolerance that can be generated by gradually increasing the dose of cocaine intermittently experienced; 3) begin an examination of the interaction between behavior maintained by conditioned reinforcement and repeated exposure to cocaine; 4) attempt to isolate factors that may have prevented the development of tolerance in our previous research; 5) continue our analysis of factors involved in the development of tolerance to behavioral stimulating effects of cocaine (most research on cocaine tolerance has involved study of response-diminishing effects of the drug); and 6) continue our attempts to isolate the crucial factors responsible for reinforcement- schedule dependent tolerance to cocaine. The study of long-term, intermittent exposure to cocaine has potential relevance to the genesis of cocaine dependence. Understanding of the processes that occur under long-term exposure should facilitate the development of effective treatment and, especially, prevention programs.